TDP-43/FUS in motor neuron disease: Complexity and challenges

Abstract

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

Keywords: Amyotrophic lateral sclerosis; FUS/TLS; Genome damage/repair; RNA processing; TDP-43.

Figure 1. Illustration of the molecular and pathological features of sporadic and familial ALS

The sporadic disease subtypes account for ~90 % of ALS cases and which could be classified based on inclusions and the protein within. In the recent years, mutations and defects in several new ALS causing genes have been implicated in distinct subgroups of ALS patients (FALS). However, proteins encoded by these genes are also found in protein inclusions/aggregates in sporadic patients (SALS). There is a distinct pattern of co-localization or overlap of pathology among the ALS-linked protein inclusions, which are indicated. *NR: not reported.

Figure 2

Schematic of TDP-43 and FUS protein structure. TDP-43 and FUS, both have a Prion-like domain, nuclear localization signal, nuclear export signal and RNA recognition motif (RRM). FUS has an additional RRM as well as a Zinc finger domain. Major familial mutations are indicated. In contrast to FUS, disease-linked TDP-43 mutations are clustered in the Glycine-rich C-terminal domain; whereas FUS disease-linked mutations are mainly clustered in the nuclear localization signal domain.

Figure 3

TDP-43/FUS in healthy neurons bind to thousands of cellular RNA’s. They shuttle between the nucleus and cytoplasm, and play roles in miRNA biogenesis, pre-mRNA splicing, mRNA stability and transport. ALS affected motor neurons present altered cytoplasmic localization and nuclear clearance of the TDP-43 and FUS, together with deregulation in their posttranslational modification states, impacting their normal functions.